Multiple intravenous tranexamic acid doses in total knee arthroplasty in patients with rheumatoid arthritis: a randomized controlled study
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Kang et al. BMC Musculoskeletal Disorders (2021) 22:425
https://doi.org/10.1186/s12891-021-04307-4
RESEARCH ARTICLE Open Access
Multiple intravenous tranexamic acid doses
in total knee arthroplasty in patients with
rheumatoid arthritis: a randomized
controlled study
Bing-xin Kang1, Hui Xu1, Chen-xin Gao1, Sheng Zhong1, Jing Zhang1, Jun Xie1, Song-tao Sun1, Ying-hui Ma1,
Xi-rui Xu1, Chi Zhao1, Wei-tao Zhai1, Lian-bo Xiao1,2* and Xiao-jun Gao1*
Abstract
Background: We aimed to determine the efficacy and safety of multiple doses of intravenous tranexamic acid (IV-
TXA) on perioperative blood loss in patients with rheumatoid arthritis (RA) who had undergone primary unilateral
total knee arthroplasty (TKA).
Methods: For this single-center, single-blind randomized controlled clinical trial, 10 male and 87 female participants
with RA, aged 50–75 years, who underwent unilateral primary TKA were recruited. The patients received one dose of 1
g IV-TXA 10 min before skin incision, followed by articular injection of 1.5 g tranexamic acid after cavity suture during
the surgery. The patients were randomly assigned (1:1) into two groups and received an additional single dose of IV-
TXA (1 g) for 3 h (group A) or three doses of IV-TXA (1 g) for 3, 6, and 12 h (group B) postoperatively. Primary outcomes
were total blood loss (TBL), hidden blood loss (HBL), and maximum hemoglobin (Hb) level decrease. Secondary
outcomes were transfusion rate and D-dimer levels. All parameters were measured postoperatively during inpatient
hospital stay.
Results: The mean TBL, HBL, and maximum Hb level decrease in group B (506.1 ± 227.0 mL, 471.6 ± 224.0 mL, and
17.5 ± 7.7 g/L, respectively) were significantly lower than those in group A (608.8 ± 244.8 mL, P = 0.035; 574.0 ± 242.3
mL, P = 0.033; and 23.42 ± 9.2 g/L, P = 0.001, respectively). No episode of transfusion occurred. The D-dimer level was
lower in group B than in group A on postoperative day 1 (P < 0.001), and the incidence of thromboembolic events
was similar between the groups (P > 0.05).
Conclusion: In patients with RA, three doses of postoperative IV-TXA further facilitated HBL and Hb level decrease
without increasing the incidence of adverse events in a short period after TKA.
Trial registration: The trial was registered in the Chinese Clinical Trial Registry (ChiCTR1900025013).
Keywords: Total knee arthroplasty, Rheumatoid arthritis, Tranexamic acid, Blood loss
* Correspondence: xiao_lianbo@163.com; 13501735927@139.com
1
Shanghai University of Traditional Chinese Medicine, Shanghai Guanghua
Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai
200052, CN, China
Full list of author information is available at the end of the article
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data made available in this article, unless otherwise stated in a credit line to the data.Kang et al. BMC Musculoskeletal Disorders (2021) 22:425 Page 2 of 8
Background randomized controlled trial, the pharmacokinetics of
Rheumatoid arthritis (RA) is an autoimmune disease tranexamic acid were determined to evaluate the efficacy
with erosive arthritis as the main clinical manifestation. and safety of multi-dose intravenous tranexamic acid
The basic pathological manifestations are synovitis, pan- (IV-TXA) in alleviating postoperative blood loss in pa-
nus formation, and gradual articular cartilage, and bone tients with RA who underwent primary unilateral TKA.
destruction, eventually leading to joint deformity and
dysfunction [1]. The main onset age for RA is 40–60 Methods
years [2]. Study design
RA disease activity measures appear to be worse in fe- This was a single-center, single-blind, randomized controlled
males than in males [3]. The use of anti-rheumatic drugs trial. The study was conducted at the Department of Ortho-
and biological agents has delayed the progress of bone pedics in Shanghai Guanghua Hospital of Integrated Trad-
destruction in patients with RA; in fact, the number of itional Chinese and Western Medicine and registered in the
RA patients receiving total knee arthroplasty (TKA) has Chinese Clinical Trial Registry (ChiCTR1900025013). The
gradually decreased over the past few decades. However, study was approved by the institutional review board (Ethics
in advanced-stage RA patients with severe knee joint de- Committee of Shanghai Guanghua Hospital of Integrated
struction, TKA is effective for improving knee function Traditional Chinese and Western Medicine). All experimen-
and quality of life [4, 5]. However, TKA can lead to tal procedures were conducted according to the Standards of
blood loss; the mean blood loss during the perioperative Reporting Trials (CONSORT) recommendations for ran-
period of TKA can reach 1470 mL [6]. Moreover, RA pa- domized controlled trials [22], and all participants provided
tients experience an increased incidence of anemia [7]. written informed consent before enrolment.
Low hemoglobin (Hb) levels before surgery also increase
the risk of blood transfusion need after surgery [8]. Con-
Sample size calculation
sidering that blood transfusion increases the risk of post-
The sample size was calculated based on the amount of
operative infections and prolongs hospital stay [9], it is
hidden blood loss (HBL) during tranexamic acid therapy.
vitally important to reduce TKA perioperative blood loss
The overall standard deviation was σ = 250, and the
and accelerate postoperative recovery. In previous stud-
allowed error estimate was δ = 200. These values were
ies, the perioperative use of multi-mode blood manage-
ment successfully reduced perioperative blood loss [10, estimated using the statistical following formula n1 ¼ n2
11]; a combination of multiple strategies of blood man- ðZ þZ Þ= 2
¼ 2 ½ a=2 δ β σ . Predicting an estimated dropout rate
agement also reduced the total blood transfusion rate
of 10%, 104 subjects would be required to yield a statis-
after TKA to less than 4% [12].
tical power of 90% with a significance level of 0.05.
Postoperative bleeding is mainly caused by fibrinolysis
due to surgical trauma. Although tourniquet application
can reduce intraoperative bleeding, fibrinolysis and post- Patients
operative bleeding will increase following the postopera- From September 2019 to May 2020, we screened pa-
tive release of the tourniquet [13]. The anti-fibrinolytic tients aged 50–75 years who underwent primary unilat-
drug tranexamic acid, by preventing the combination be- eral TKA for RA, using doppler ultrasound and
tween plasminogen and fibrin, protects fibrin from deg- computed tomography examination to identify patients
radation by plasmin to achieve hemostasis [14]. Clinical without deep vein thrombosis (DVT) and pulmonary
studies have confirmed that tranexamic acid can reduce embolism (PE), respectively. The exclusion criteria in-
the incidence of anemia after TKA and reduce transfu- cluded a diagnosis of other types of arthritis (i.e., not
sion rate without elevating the incidence of venous RA), renal dysfunction, or severe cardiovascular or cere-
thrombosis [15–18]. A meta-analysis showed that 2 g brovascular diseases; patients who reported prolonged
tranexamic acid had the best effectiveness and safety use of oral anticoagulant drugs were also excluded. The
profile [19]. However, there is still no consensus on the elimination criteria included acquired color vision dis-
optimal dose and timing of tranexamic acid administra- order, active intravascular coagulation patients, and a
tion [20]. history of seizures.
Patients with RA may experience mild to moderate
anemia; thus, they have a higher risk of infection at the Randomization and drug administration
surgical site than that in patients with OA [21]. We hy- All eligible patients were randomized into two groups
pothesized that high drug doses will be beneficial for RA using computer-generated randomization by a statisti-
patients undergoing TKA. In our orthopedic depart- cian who was not involved in the trial. The group data
ment, enhanced recovery after surgery is strongly advo- were saved by the statistician. The allocation was con-
cated, for which blood management is essential. In this cealed in consecutively numbered, sealed, opaqueKang et al. BMC Musculoskeletal Disorders (2021) 22:425 Page 3 of 8
envelopes. IV-TXA (1 g) was administered 10 min before temperature, with the knee joint able to be activity
skin incision by an anesthesiologist, and tranexamic acid flexed by more than 90 degrees; Hb level > 70 g /L
(1.5 g dissolved in 10 mL of normal saline) was adminis- was an additional criterion.
tered via articular injection by a surgeon after cavity su- During hospitalization, all patients received physical
ture during the surgery. Patients in group A received prophylaxis and chemoprophylaxis for venous thrombo-
one dose of IV-TXA (1 g) 3 h postoperatively, while embolism. The patients were asked to perform equal-
those in group B received three doses of IV-TXA (1 g) 3, length contractions of the femoral quadriceps, ankle
6, and 12 h postoperatively. The doses were administered pump movements, lower-extremity strength training,
by a nurse after surgery. The surgeon, anesthesiologist, and motion exercises on the day after surgery. At 6 h
and statistician were blinded to the trial. Only the nurses after surgery, perioperative oral rivaroxaban (10 mg,
knew the patients’ group assignment. Tranexamic acid once a day for 14 days) was prescribed to prevent throm-
was produced from Hunan Dongting Pharmaceutical bosis [25]. Blood transfusions was administered to pa-
and used according to the second edition of the 2015 tients with postoperative Hb level of less than 70 g/L or
Chinese Pharmacopoeia and Drug Supplement Applica- any organ dysfunction related to anemia regardless of
tion Approval (2013B02016), YBH07372010, under the Hb level [26].
National Drug Standard approval number H43020565.
Perioperative anti-rheumatic treatment Outcome measures
Methotrexate and hydroxychloroquine were used during Perioperative hematocrit (Hct) and Hb levels, coagula-
the perioperative period. Leflunomide was discontinued tion index, and renal function were measured preopera-
at 1 week before surgery. The use of other disease- tively and on POD 1, 3, 7, and 14.
modifying anti-rheumatic drugs was discontinued 2 days The Nadler formula [27] was used to estimate patient
before surgery and restarted at 1–2 days after gastro- blood volume (PBV), and the Gross [28] formula was
intestinal function recovery. The use of newer biologic used to calculate blood loss based on PBV and Hct level
agents, such as tumor necrosis factor-alpha, was discon- reduction.
tinued at four to five half-lives before surgery and Intraoperative blood loss (IBL) was estimated based on
restarted after wound healing and elimination [23, 24]. the amount of liquid in the negative pressure drainage
bottle + the amount of liquid in the gauze – the amount
Preoperative Anemia treatment of saline. a piece of soaked gauze contained approxi-
Patients with preoperative Hb level < 12 g/dL were ad- mately 20 mL of the liquid.
ministered erythropoietin 10,000 U orally once a day; the PBV = K1 × height3 (m3) + K2 × weight (kg) + K3. For
Hb level was checked regularly, and the administration males: K1 = 0.3669, K2 = 0.03219, K3 = 0.6041. For fe-
was stopped when Hb level reached > 15 g/dL. males: K1 = 0.3561, K2 = 0.03308, K3 = 0.1833. Total red
blood cell loss (TBL) = PBV × (Hctpre – Hctpost)/Hctave,
Surgical procedure and postoperative management where Hctpre = initial pre-operative Hct level, Hctpost =
For perioperative prophylaxis, cefazolin sodium antibi- lowest Hct postoperative, Hctave = average of Hctpre and
otics were administered 30 min before and 24–48 h Hctpost. HBL is defined as TBL minus IBL plus transfu-
after surgery. General anesthesia was administered by sion. Thus, HBL = TBL – IBL + transfusion.
an anesthetist. Blood pressure was controlled to The follow-up time was 14 days after surgery. Patients
within 80–100 mmHg/60–70 mmHg throughout the were monitored for adverse events (e.g., DVT, PE,
procedure. Tourniquet was inflated to 100 mmHg wound complications, infection, and acute renal failure).
above the systolic pressure before incision and de- Transfusion rate and adverse events were assessed post-
flated after incision closure. The surgery was per- operatively during the inpatient hospital stay.
formed by a single surgeon using the same technique.
All patients received a surgeon-selected, cemented,
posterior-stabilized prosthetic design with patellar re- Statistical analysis
surfacing. Drains and blood salvage after surgery were Analyses were performed using SPSS Version 25.0 (IBM
not performed for these patients. Postoperatively, the Corp., Armonk, New York). Data of continuous variables
elastic bandage was compressed, and the operated were evaluated for normal distribution using the Shapiro-
limb was bandaged for 24 h. The patients were dis- Wilk test and presented as means ± standard deviations
charged on post-operative day (POD) 14 provided (SDs). Differences between groups were compared using
they met the discharge criteria. The discharge criteria two independent sample t-tests. Pearson’s chi-square test
included well-healed wound, no wound leakage, no was used to analyze categorical variables. P-values of less
infection, no swelling, no pain, and normal body than 0.05 indicated statistical significance.Kang et al. BMC Musculoskeletal Disorders (2021) 22:425 Page 4 of 8
Results Discussion
Patient characteristics Our results revealed the effectiveness of three regimens
Between September 2019 and May 2020, a total of 104 of tranexamic acid therapy in reducing postoperative
participants were assessed for eligibility. They were ran- HBL in RA patients. The stress-induced damage of per-
domized homogeneously into two groups (52 in group A ipheral blood vessels caused by operation and the use of
and 52 in group B) to receive the study medication. The a tourniquet during operation promotes the occurrence
duration of follow-up was 2 weeks. A total of 7 patients of postoperative fibrinolysis and increases the amount of
were drop-out owing to the following reasons: 3 patients HBL due to the blood lost into the tissue intraopera-
were discharged within 10 days; 1 had an infection, and tively and postoperatively, accounting for approximately
3 refused to receive blood products (Fig. 1). Patient 50% of the TBL [29]. With the reduction of the tourni-
demographics and per- and intra-operative variables quet, the fibrinolysis around the wound reached a peak
were compared between the two groups (Table 1). within 6 h and was maintained for 18 h [30]. The half-
life of tranexamic acid in plasma is 2–3 h [14], and its
Blood loss, maximum Hb drop, and transfusion rate antifibrinolytic effect is maintained for approximately 8 h
The decrease in the mean TBL, HBL, and Hct and Hb [31]; after intravenous administration, its 24 h recovery
levels was lower in group B than in group A. The D- from urine is approximately 90% [14]. We repeated IV-
dimer levels was lower in group B than in group A on TXA three times postoperatively to ensure that the con-
POD 1. For-three-patients in group A and 40 patients in centration of TXA in the plasma was maintained. Based
group B received EPO. There was on significant differ- on in vivo and in vitro data, the effective therapeutic
ence between the group. None of patients received a plasma concentration of tranexamic acid in inhibiting fi-
blood transfusion during the follow-up period (Table 2). brinolysis has been determined to be 5–10 mg/L or 10–
15 mg/L [31, 32].
Complications and adverse events Considering the pharmacological characteristics of
All incisions were healed by the first intention, and no tranexamic acid, a single dose of IV-TXA (1 g) after sur-
patient developed DVT, PE, acute renal failure, or other gery may not achieve the maximum antifibrinolytic ef-
adverse events. There were no statistically significant dif- fect. Although it has been reported that tranexamic acid
ferences in calf vein thrombosis and superficial infection does not reduce the rate of blood transfusion after joint
between the two groups (P > 0.05; Table 3). replacement in patients with RA [33], we investigated
Fig. 1 Consolidated Standards of Reporting (CONSORT) flow diagram. Name of the registry: Clinical observation of multiple dose administration
of tranexamic acid in patients with rheumatoid arthritis after total knee arthroplasty. Prospective registration, ChiCTR1900025013. Registered 7
August 2019,Kang et al. BMC Musculoskeletal Disorders (2021) 22:425 Page 5 of 8
Table 1 Preoperative and intraoperative characteristics of the patients
Variable Group A Group B P-value
Mean ± SD (n = 48) (n = 49)
Patient characteristics
Age (y) 66.4 ± 5.9 66.5 ± 5.5 0.921a
Gender (male/female), 4/44 6/43 0.529b
Body mass index (kg m−2) 21.8 ± 3.4 22.4 ± 3.1 0.397a
Patient blood volume (mL) 3487.7 ± 512.9 3525.3 ± 520.5 0.721a
Preoperative laboratory values
Hematocrit (%) 36.1 ± 3.2 36.9 ± 3.7 0.215a
Hemoglobin (g/L) 117.5 ± 13.9 119.2 ± 14.8 0.565a
9
Platelets (× 10 /L) 232.6 ± 60.6 226.3 ± 60.2 0.605a
D-dimer (mg/L) 1.1 ± 0.6 1.0 ± 0.5 0.623a
Activated partial thromboplastin time (s) 26.3 ± 4.0 25.9 ± 3.6 0.685a
Fibrinogen (g/L) 3.6 ± 0.9 3.7 ± 1.1 0.608a
Prothrombin time (s) 11.5 ± 0.8 11.3 ± 0.6 0.191a
International normalized ratio 1.0 ± 0.1 1.0 ± 0.1 0.294a
Erythrocyte sedimentation rate (mm/h) 38.0 ± 18.8 37.1 ± 19.8 0.819a
C-reactive protein (mg/L) 11.2 ± 7.3 11.4 ± 6.4 0.902a
Intraoperative blood loss (mL) 34.8 ± 6.8 34.5 ± 7.1 0.842a
a
Two independent sample t tests
b
Pearson’s chi-square test
three postoperative doses of IV-TXA (1 g). Our results 159 patients and claimed that a five-dose regimen could
have shown that the concentration of blood and antifi- further reduce the blood loss, minimize inflammation,
brinolytic effect of tranexamic acid were maintained dur- enhance mobility, and shorten the length of hospital
ing the whole process of fibrinolysis. Decrease in HBL as stay, without increasing the risk of DVT and PE. Maniar
well as Hct and Hb levels during hospitalization were and colleagues [7] conducted a prospective randomized
lower with multiple doses than with a single dose. Hct controlled trial in 240 patients and claimed that a three-
and Hb levels in both groups decreased to the lowest dose regimen was more successful than a single-dose
level on POD 3, indicating that HBL persisted 3 days regimen, and a two-dose administration could be the
after surgery. least effective regimen in reducing TBL.
Multiple strategies have been developed to reduce To the best of our knowledge, this is the first random-
blood loss in the perioperative period, including pre- ized controlled study to investigate the efficacy of multi-
operative anemia assessment, minimally invasive surgery, dose tranexamic acid after TKA in reducing postoperative
shortening of the operation time, use of antifibrinolytic HBL in patients with RA. Although our results differ from
drugs, and postoperative nutritional supplement. Conse- those of Good et al. [37], we believe that a postoperative
quently, the number of patients requiring blood transfu- adequate dose of tranexamic acid administered at least
sion after the operation has been decreasing. three times can effectively reduce HBL after surgery.
Many studies have shown that repeated administration Unlike OA patients, RA patients highly express high
of postoperative tranexamic acid (mainly in OA patients) levels of inflammatory factors, such as IL-1, IL-6, and
is not associated with an increased risk of venous TNF- α, which leads to the upregulation of procoagulant
thromboembolic events [16, 34, 35]. Tzatzairis et al. [16] factors and downregulation of anticoagulation factors
showed that during TKA without the use of tourniquet, [38]. Thus, repeated postoperative administration of IV-
three doses of perioperative IV-TXA (15 mg/kg) reduced TXA may increase the incidence of DVT and PE. We
blood loss, Hb level decrease, and transfusion rate, lead- evaluated the occurrence of DVT and PE by observing
ing to faster rehabilitation. Sun et al. [36] showed that the clinical symptoms of patients, D-dimer levels, Dop-
the administration of a total dose of 30 mg/kg tranex- pler ultrasound data, and pulmonary computed tomog-
amic acid preoperatively combined with the administra- raphy data. The results showed that the average level of
tion of tranexamic acid twice postoperatively was more D-dimer in group A was significantly higher than that in
effective in reducing postoperative blood loss. Lei et al. group B within 1 day after surgery, indicating that three
[18] conducted a randomized controlled trial involving doses of postoperative IV-TXA could fibrinolysis andKang et al. BMC Musculoskeletal Disorders (2021) 22:425 Page 6 of 8
Table 2 Primary and secondary outcomes of regarding occurrence of DVT [39]. D-dimer levels can increase
laboratory values after surgery under trauma, inflammation, and surgery [40]. Conven-
Variable Group A Group B P-value* tionally, D-dimer level of higher than 0.5 mg/L is the
Mean ± SD (n = 48) (n = 49) cut-off value for the diagnosis of venous thrombosis;
Primary outcomes however, D-dimer level naturally increases with age, and
Total red blood loss (mL) 608.5 ± 239.9 506.1 ± 227.0 0.038 in patients aged more than 50 years, the D-dimer cut-off
Hidden red blood loss (mL) 571.0 ± 237.3 471.6 ± 224.0 0.036 value is defined as the patient’s age times 10 μg/L [41].
Maximum hemoglobin drop 23.7 ± 9.4 17.5 ± 7.7 < 0.001
The occurrence of venous thrombosis can be safely ruled
out in patients with no symptoms of venous thrombosis,
Secondary outcomes
as their D-dimer level is lower than normal [42]. The de-
Transfusion (%) 0 0 – termination of D-dimer level is recommended for pa-
Postop. laboratory values tients with a low or moderate clinical probability of
Hematocrit (%) DVT [43].
POD 1 32.8 ± 2.8 34.1 ± 3.5 0.040 According to the Chinese expert guidelines for the
POD 3 30.4 ± 2.6 32.5 ± 3.4 0.001
prevention of venous thrombosis after TKA, anticoagu-
lants should be used for at least 10–14 days, and postop-
POD 7 31.8 ± 3.1 33.5 ± 3.5 0.014
erative lower limb functional rehabilitation training
POD 14 33.8 ± 2.8 34.4 ± 3.0 0.346 should be performed to prevent the occurrence of ven-
Hemoglobin (g/L) ous thrombosis [44]. Studies have shown that under the
POD 1 105.0 ± 9.3 108.7 ± 12.4 0.108 contemporary prophylactic regimens, the incidence of
POD 3 94.2 ± 9.3 102.2 ± 11.8 < 0.001 DVT and PE after TKA is very low [45], the top-ranking
POD 7 101.5 ± 10.6 106.8 ± 12.3 0.024
intervention for preventing DVT being rivaroxaban [46].
A tourniquet can decrease intraoperative bleeding and
POD 14 109.2 ± 8.8 110.4 ± 10.2 0.542
facilitate bone-prosthesis adhesion, but it can also in-
D-Dimer (mg/L) crease HBL after operation [47]. Some studies have also
POD 1 5.5 ± 2.9 1.0 ± 0.5 < 0.001 shown that a tourniquet increases the degree of pain for
POD 3 3.8 ± 1.8 3.8 ± 2.1 0.998 a short time after surgery, but it does not increase the
POD 7 3.6 ± 1.4 3.1 ± 1.4 0.085 recovery time of knee function after TKA [48]. We used
POD 14 2.9 ± 1.2 2.7 ± 1.2 0.326
a tourniquet during operation and administered multi-
* dose tranexamic acid antifibrinolytic therapy after the
Two independent sample t tests. POD1 post-operative day 1, POD3 post-
operative day 3, POD7 post-operative day 7, POD14 post-operative day 14 operation. Our results showed that our perioperative
blood management program can achieves a balance be-
inhibit fibrinolysis effectively, thereby reducing HBL tween bleeding and hemostasis as well as anticoagulation
after surgery. and anti-fibrinolysis effects.
The D-dimer level reflects changes in blood coagula- There are, however, some limitations to the present
tion and fibrinolysis in the body. An increase in D-dimer study. Firstly, due to the incidence of RA in females being
level is an indicator of hypercoagulability and hyperfibri- higher than that in males, there was an uneven male to fe-
nolysis and a preferred index for determining the male ratio; there were more female than male patients in
the study. We plan to conduct future clinical studies to re-
duce the impact of sex on the study results. Second, owing
Table 3 Complications to postoperative blood loss and ethical considerations, we
Variable Group A Group B P-value did not establish a placebo group to evaluate the effective-
(n = 48) (n = 49)
ness of tranexamic acid. Third, the examination period of
Deep vein thrombosis 0 0
postoperative outcomes was not strictly 24 and 72 h after
Pulmonary embolism 0 0 operation; thus, we are planning to design another study
Calf muscular vein thrombosis 3 4 0.717a to obtain more accurate results. Fourth, functional recov-
Superficial infection 1 0 0.312a ery of the knee after surgery was not evaluated in this
Deep prosthetic infection 0 0 study. Finally, we performed only lung CT to examine pa-
Shock 0 0
tients with symptoms to determined whether there was
PE. Although the half-life of tranexamic acid is short, the
Cardiac infarction 0 0
short follow-up time may not be adequate to fully assess
Wound complications 0 0 the risk of DVT and other complications after multiple
Acute renal failure 0 0 doses of IV-TXA in patients with RA; extending the
a
Pearson’s chi-square test follow-up period will be considered in future studies.Kang et al. BMC Musculoskeletal Disorders (2021) 22:425 Page 7 of 8
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